Although the pathophysiologic manifestations of sickle cell disease has been assumed to result from vaso-occlusion secondary to the rheologically-abnormal erythrocytes, actual blood vessel obstruction has been rarely demonstrated in vivo. With the development of new non-invasive imaging and para-imaging methods, it is now technically possible and feasible to characterize both regional organ perfusion and tissue biochemistry in quantitative terms, and in addition attempt to reconstruct the pathophysiologic events responsible for initiation, ischemia, infarction and resolution in these patients. Our goals are to develop ways to examine the pathophysiological processes in various organs, to develop quantitative ways to assess disease severity and progression, and to develop objective means to evaluate potential therapeutic approaches. In preliminary analyses of anaerobic threshold measurements we have found that the vasodilator, nifedipine, increases the time of exercise before the occurrence of sustained anaerobiosis. After calibrating an analytical method to derive the distribution of intracellular hemoglobin concentrations presesnt in the peripheral blood of sickle cell patients, we were able to demonstrate that the pathognomonic conjunctival "comma" sign relates to the extent of the red cell heterogeneity. Using the technique of laser-Doppler velocimetry, we have found that forearm cutaneous microcirculatory flow undergoes a unique characteristic periodic pattern. Preliminary studies of 2-deoxy-18 fluoro-deoxyglucose brain metabolism suggest that there are regional and hemispheric topographical abnormalities when compared to age-matched controls. Feasibility studies are currently underway to determine the utility of nuclear magnetic resonance imaging in these patients. These studies should facilitate clinical trials of therapeutic agents designed to maintain or improve the biological integrity of jeopardized organs in patients with sickle cell disease. We plan to extend these studies to patients with other sickle cell syndromes.